It is estimated that 8.3 million people suffer from active gout in the U.S.1 The incidence and prevalence of gout is rising. This is due to factors such as an increase in the aged population, many of whom take thiazide diuretics and prophylactic aspirin that promote hyperuricaemia and lifestyle factors characterized by diets that include excessive fructose and alcohol intake, physical inactivity and abdominal fat accumulation which favor hyperuricaemia.2,3 
The impaired renal excretion of uric acid is the dominant cause of hyperuricaemia in the majority of patients with gout.4 The existence of genetic variants within a transport gene, SLC2A9, have been reported that explain 1.7% to 5.3% of the variance in serum urate concentrations in a Croatian population sample.5 SLC2A9 variants have also been associated with a low fractional excretion of urate and the presence of gout in several other European population samples.6 The SLC2A9 gene is found on human chromosome 4 and encodes the facilitative glucose transporter 9 (Glut9), which is a unique hexose and high-capacity urate transporter.7 It has been shown that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron in the mouse.8 Glut9 sustains urate reabsorption in the kidney independently of the other known urate transporters URAT1, OAT1, and OAT3.8 
It has been found recently that human ATP-binding cassette, subfamily G, member 2 (ABCG2), encoded by the ABCG2 gene, is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion.9 Introduction of a mutation encoded by a common ABCG2 SNP (rs2231142) in Xenopus oocytes resulted in a 53% reduction in urate transport rates compared with wild-type ABCG2. The data obtained in a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region, exhibiting highly significant associations with urate concentration. These findings suggest that this SNP has a significant pathogenic role in at least 10% of all gout cases in white persons.9 It has been confirmed in a study in Japanese patients that common nonfunctional mutations of ABCG2 are involved in the pathology of gout.10 
The risk of developing gout is related to the degree of hyperuricaemia11, 12 and increases rapidly after the serum urate concentration exceeds ˜400 μmol/L which is close to the level at which monosodium urate (MSU) crystals precipitate out of serum in vitro.13 It has been established that phagocytosed intracellular MSU crystals are detected in the cytoplasm by the NALP3 inflammasome in monocytes or macrophages.14 The result is activation of caspase-1, which initiates IL-1β maturation and secretion. In turn, interleukin IL-1β secretion produces various pro-inflammatory mediators, which elicit neutrophil influx into the joints.14 The results of in-vivo studies have confirmed that IL-1β and its pathway is crucially associated with the inflammatory response induced by MSU crystals, suggesting that IL-1β is a pivotal mediator of inflammation in acute gout as well as chronic gout and a key therapeutic target.15, 16. 
The first-line urate-lowering therapy for the treatment of gout over the past four decades has been allopurinol which lowers serum urate levels by the inhibition of xanthine oxidase.17 The FDA guidelines recommend increasing the dose progressively from an initial dose of 100 mg a day to a maximum of 800 mg a day until the target serum urate (SU) level of ≦6 mg/dL ((˜357 μmol/L) is achieved.18 However, the vast majority of allopurinol prescriptions are for doses of 300 mg a day or less. This situation has been promoted by the persistence of longstanding non-evidence based dosing guidelines that were originally designed to avoid the allopurinol hypersensitivity syndrome without any consideration for efficacy.18 
Febuxostat (Ulloric®, Takeda) is a urate lowering therapy recently approved by the FDA for the treatment of chronic gout. It is a non-purine-analogue inhibitor of xanthine oxidase that lowers circulating uric acid levels.17 It was found that febuxostat was more effective than allopurinol in attaining appropriate SU levels (<360 μmol/L), but 59% of patients who previously failed to normalise uric acid levels <360 μmol/L) on allopurinol also failed on febuxostat 80 mg/day.19 Febuxostat is an alternative for patients for whom allopurinol is relatively contraindicated, due to a lack of evidence-based studies, particularly in mild to moderate renal dysfunction where dose modification is not required. The main side effects of febuxostat include raised hepatic enzymes and a small increase in the rate of serious cardiovascular events which preclude its use in ischaemic or congestive heart failure.
The ageing of the population and the proliferation of unhealthy lifestyles together with the sub-optimal use of allopurinol and uncertainty concerning the place of febuxostat emphasises the need for new drugs for the treatment of gout.
The present inventor has realised that the recent advances in the molecular genetics of renal urate transporters together with the discovery of the inflammasome may offer the opportunity to develop novel therapeutic agents based on the identification of specific targets that are involved in the pathology of gout.
Bucillamine, (Rimatil®, N-(2-mercapto-2-methylpropionyl)-L-cysteine) is manufactured by Santen Pharmaceutical Co. Ltd. It is a disease-modifying anti-rheumatic drug which is used as a first-line treatment for rheumatoid arthritis in Japan.20 Bucillamine is a member of a group of low molecular weight, cysteine-derived thiol donors that includes N-acetylcysteine and N-2-mercaptopropionyl glycine.21, 22 These compounds readily enter cells through the cysteine transport pathway and exert their antioxidant effect by maintaining the endogenous glutaredoxin (Gtx) and thioredoxin (TRx) systems in a reduced state by transfer of thiol groups.21, 22 Bucillamine contains two donatable thiol groups, making it a considerably more potent antioxidant than N-acetylcysteine or N-2-mercaptopropionyl glycine which each contain only one thiol group.23-25 The present inventor has appreciated that in addition to its direct antioxidant action, bucillamine also increases the transcriptional activity of Nrf2.26

The physiological importance of ABCG2 in humans is illustrated by the large differences in SU levels and the prevalence of gout caused by genetic variation in ABCG2. It is therefore, a potential target for new uricosuric agents in the treatment of gout.9, 10 It has been shown that ABCG2 (BCRP) is induced by the Nrf2 activators oltipraz in primary human hepatocytes27 and tert-butylhydroquinone in HepG2 cells.28 
The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as a unidirectional efflux pump for urate with multiple allosteric substrate binding sites located at the apical membrane of kidney proximal tubules.29 The treatment of wild-type and Nrf2-null mice with oltipraz and butylated hydroxyanisole demonstrated that the induction of ABCC4 was Nrf2-dependent.30 Oltipraz also induces ABCC4 (MRP4) mRNA and protein expression in HepG2 cells and primary human hepatocytes via the Nrf2 transcription pathway.31 
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.